Autosomal recessive polycystic kidney disease (ARPKD) is an inherited disorder that usually presents in the newborn period with massive kidney enlargement (due to rapidly expanding cysts) and hepaticfibrosis. ARPKD occurs in approximately 1:10,000 to 1:40,000 births and produces significant morbidity and mortality. Data from experimental models of both recessive and dominant forms of PKD have identified three key pathophysiologic processes in cyst formation and enlargement: increased cell proliferation, increased fluid secretion and altered matrix biology. (Marcia N S, Sweeny W E Armer E D: New insights into the molecular pathophyscology of polycystic kidney disease, Kidney Int, 55:1187-1197, 1999). A growing body of evidence has established the central role of the epidermal growth factor receptor (EGFR) in the pathogenesis of cell proliferation in PKD.
Published reports have also suggested that transforming growth factor-α (TGF-α) a ligand of the EGFR, is abnormally expressed in PKD. Mice transgenic for TGF-α develop renal cysts. TGF-α is present in mitogenic quantities in cyst fluid from bpk mice (a murine model of ARPKD) and immunoprecipitation of TGF-α reduces this mitogenic effect (Abstract; J Am Soc Nephrol 7:1610, 1996).
U.S. Pat. No. 6,002,008 discloses that certain EGF receptor kinase inhibitors are useful in the treatment of PKD; however no disclosure of the present invention is disclosed therein.
There is currently no completely effective therapy for polycystic kidney disease. A search for therapeutic agents useful for the treatment of PKD is ongoing.